Rates of depression and anxiety are greater among individuals with type 2 (insulin resistant) diabetes. Diabetes is associated with an increased prevalence of clinical depression. Changes in brain structure in diabetes occur within temporal lobe circuits that are also sensitive to stress-related mood disorders. Diabetics exhibit hippocampal atrophy, particularly in the dentate gyrus subfield, and hippocampal atrophy is associated with changes in memory and mood regulation in this population. Given the established role of hippocampal activity in appropriate termination of the hypothalamic-pituitary-adrenal axis (HPA axis) response to stress, it is likely that there is some mechanistic relationship between impairment of hippocampal function and HPA axis dysregulation in insulin resistant individuals. The studies in this proposal are designed to determine whether hippocampal atrophy disinhibits the HPA axis, initiating a cycle of glucocorticoid- mediated synaptic impairment in a genetic mouse model of obesity and insulin resistance. We will test this model using leptin receptor mutant mice (db/db mice), which are obese and diabetic and exhibit elevated levels of corticosterone, the primary glucocorticoid in rodents. Hippocampal brain-derived neurotrophic factor (BDNF) expression is significantly reduced and we have preliminary data demonstrating that negative feedback on the adrenocortical response to stress is impaired in db/db mice. We plan to manipulate BDNF expression using a lentivirus to determine the network consequences of alterations in hippocampal neurotrophic factor expression for HPA axis negative feedback. We will measure markers of neural activation in chemically identified neuronal populations to evaluate recruitment along the circuitry mediating HPA axis shutoff after restraint stress. These studies in leptin receptor deficient mice could elucidate mechanisms related to the comorbidity between diabetes and depression in human populations.